Notch Inhibitor Shows Modest Efficacy

Data from a phase I study indicate that LY3039478 (Eli Lilly), an investigational Notch-signaling inhibitor, is modestly effective against a range of cancers, including rare types such as adenoid cystic carcinoma (ACC). The findings were presented by Christophe Massard, MD, during the 2016 EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics, held November 29–December 2 in Munich, Germany.

“There are different ways to target this pathway, including blocking Notch ligands with monoclonal antibodies,” said Massard, who chairs the early drug development program at Institut Gustave Roussy in Villejuif, France. Another way is to inhibit the enzyme γ-secretase, which LY3039478 is designed to do, he explained. Normally, γ-secretase cleaves Notch's intracellular domain, which then translocates to the nucleus and activates signaling.

Massard reported results on 110 patients with breast cancer, leiomyosarcoma, and ACC, among other tumor types. All had advanced or metastatic disease with NOTCH mutations or amplifications, determined through molecular screening. Several patients with FBXW7 mutations were also enrolled; Massard noted that aberrations in this gene “appear to increase activation of Notch signaling.”

The investigators initially set LY3039478's dosing schedule at 75 mg, three times a week, which was later reduced to 50 mg to lessen gastrointestinal toxicities that many patients found intolerable. The drug's other main side effects included thrombocytopenia and fatigue.

One patient with infiltrating ductal carcinoma, a common breast cancer, that had an FBXW7 mutation experienced tumor shrinkage after two cycles of LY3039478—her confirmed partial response lasted 9.4 months. An unconfirmed partial response was seen in a patient with metastatic ACC whose tumor was considered metabolically inactive after treatment, based on PET. Another 10 patients had stable disease for at least 6 months, including one with leiomyosarcoma who experienced “quite impressive tumor necrosis” with LY3039478, Massard said.

Discussing the data, Gordon Mills, MD, PhD, who was not involved in the study, observed that an independent molecular analysis by his group uncovered NOTCH defects in approximately 9% of 11,042 tumor specimens from The Cancer Genome Atlas. “So, there's a significant number of patients who stand to benefit from a good Notch inhibitor,” said Mills, chair of systems biology at The University of Texas MD Anderson Cancer Center in Houston. Besides LY3039478, multiple Notch inhibitors are in clinical trials, he said, including a few that have progressed beyond phase I.

Mills cautioned that “because Notch can act as a tumor suppressor or as an oncogene, determining which aberrations are activating versus inactivating will be very important when it comes to selecting patients for targeted therapy.” Noting LY3039478's modest activity overall, he added that designing combination trials “for these types of inhibitors that have an early but not striking signal” will also be key “to truly demonstrate their benefit.”

Massard said that he and his colleagues plan to test LY3039478 in combination with other drugs, including the investigational agents taladegib (Ignyta), which suppresses Hedgehog/Smoothened, and abemaciclib (Eli Lilly), a CDK4/6 inhibitor. –Alissa Poh